The first line of defense against HIV-1 infections and the primary site for their transmission are mucosal surfaces of the oral cavity and the genital, and gastrointestinal tracts. The rate of HIV-1 transmission through oral cavity is significantly lower than the transmission through the genital or intestinal routes, although it still carries a risk. To address the question of oral resistance or susceptibility to HIV-l-infection, this application focuses on the cellular factors that reduce the transmission rate in oral cavity. Specifically, we propose to: 1. Establish whether oral epithelia are less capable of transferring HIV-1 from infected lamina propria cells into oral secretions than the genital or rectal epithelia. To accomplish this aim, approximately 50, primarily HIV-1 infected adults, not taking ART medication will be enrolled and asked to donate saliva, intestinal, cervicovaginal or seminal fluids and peripheral blood. Differences occurring between the HIV-1 released in saliva vs. the genital or rectal secretions, will be determined in the same individual with respect to: a) levels of free and cell-associated virus; b) its capacity to generate a productive infection; c) phenotype(s) (X4 or R5) of infectious viruses, and type of cells containing HIV-I. 2. Determine whether the expression of HIV-1 receptors and co-receptors and of relevant adhesion molecules on oral epithelia causes them to be less effective than the genital or rectal epithelia in transferring HIV-lfrom the apical surface to the subepithelial target cells. Differences in CD4, GaI-Cer, CCR5, CXCR4, ICAM-2 and ICAM-3 expression and the distribution of HIV-1 target cells will be ascertained on explant tissues of oral, rectal and genital origin. Moreover, their potential of epithelia to selectively transport/be infected and generate a productive infection by HIV-1 phenotypes in free or cell-associated forms will be determined. Finally, by means of epithelial cell lines, it will be established whether the free HIV-1 receptors and co-receptors released from the oral epithelial cells can prevent the access of HIV-1 to its target cells. The data generated will contribute to the understanding of mucosal HIV-1 transmission.